Project Summary Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. Acellular biodegradable materials are promising for MI treatment by providing temporary mechanical support and bioactive stimulation without cellularization. However, recruiting sufficient repair cells in harsh ischemic area for tissue regeneration is a big challenge for such acellular materials. Cell homing technique has been confirmed to recruit stem cells to the infarction site by controlled releases of chemokines such as the stromal cell-derived factor 1 alpha (SDF- 1?). However, the local harsh environment proved to interfere the timely cardiovascular differentiation of the recruited stem cells, which is critical for myocardial repair after infarction. Recently, several research groups have reported that porcine heart derived extracellular matrix (ECM) hydrogel promoted embryonic stem cell differentiation into cardiomyocytes without additional chemical induction. Furthermore, when the ECM hydrogel has been injected into the porcine infarcted heart, promising results have been observed in term of cardiomyocyte infiltration and heart function restoration. Based on the above evidences, we hypothesize that acellular injectable systems with long term release profiles of stem cell recruitment factors and the capability of cardiovascular induction will significantly increase the repair cells in the heart, accelerate cardiac repair and improve cardiac functions after myocardial infarction. Our goal for this project is to test this hypothesis using a bioactive injectable blends, which will be developed by combining tissue decellularization and nanoparticle- based drug delivery technologies. To achieve our goal, two specific aims will be pursued: 1) fabricate the bioactive injectable blends for cardiac stem cell recruitment and directed cardiovascular differentiation; and 2) determine efficacy of the bioactive injectable blends using a rat model of myocardial infarction. The innovation aspects of this project include that 1) it develops a bioactive injectable blends which synergizes stem cell recruitment with the bioactivity of cardiac ECM, 2) the developed bioactive injectable blends enables the further improvement of current stem cell recruitment strategies for tissue repair and regeneration, and 3) the proposed injectable blends is translational. The project provides new materials and methodologies to treat heart infarction, which can also be utilized for other tissue regeneration purposes. Furthermore, this project will offer learning and training opportunities to underrepresented students in biomaterial and tissue engineering, and provide a biomaterial platform for cross-institutional collaboration in Dallas-Fort Worth area.